A nitrergic secretomotor neurotransmitter in the chloride secretory response to serotonin

The neural secretory response to serotonin is mediated by enteric nerve-based 5-HT3 receptors via a nonadrenergic, noncholinergic neurotransmitter. We hypothesize that nitric oxide (NO) is this neurotransmitter, acting through cGMP at the secretory cell level to induce chloride secretion in the rat distal colon. Chambered colon was exposed to the 5-HT3 agonist, 2-methyl-5-HT, in the presence and absence of potent neural nitric oxide synthase (nNOS) inhibitors, quantifying changes in short-circuit current (delta I(SC)). Isotopic chloride efflux was measured in isolated colonocytes treated with a NO* donor (DNO) or cGMP analogue in the presence and absence of a guanylyl cyclase antagonist. Cyclic GMP production was quantified in both models. Pretreatment with potent nNOS antagonists significantly reduced the concentration-dependent 2-methyl-5-HT-induced delta I(SC). 2-Methyl-5-HT caused significant cGMP production. DNO induced cGMP production and cGMP-dependent chloride efflux in colonocyte populations. These data indicate that NO is a secretomotor neurotransmitter in response to serotonin.